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L J Ptácek

Publications and source records attributed to L J Ptácek.

At least 19 recordsLinked to original sources
PubMed2007

Modeling of a human circadian mutation yields insights into clock regulation by PER2.

Circadian rhythms are endogenous oscillations of physiological and behavioral phenomena with period length of approximately 24 hr. A mutation in human Period 2 (hPER2), a gene crucial for resetting the central clock in response to light, is associated with familial advanced sleep phase syndrome (FASPS), an autosomal dominant condition with early morning awakening and early sleep times. The FASPS hPER2 S662G mutation resulted in PER2 being hypophosphorylated by casein kinase I (CKI) in vitro. We generated transgenic mice carrying the FASPS hPER2 S662G mutation and faithfully recapitulate the human phenotype. We show that phosphorylation at S662 leads to increased PER2 transcription and suggest that phosphorylation at another site leads to PER2 degradation. Altering CKIdelta dosage modulates the S662 phenotype demonstrating that CKIdelta can regulate period through PER2 in vivo. Modeling a naturally occurring human variant in mice has yielded novel insights into PER2 regulation.

Amino Acid Sequence↗
PubMed2006

Andersen-Tawil syndrome: definition of a neurocognitive phenotype.

BACKGROUND: The Andersen-Tawil syndrome (ATS) is a potassium ion channelopathy caused by mutations in the KCNJ2 gene. It is characterized by periodic paralysis, cardiac arrhythmias, and distinctive features; the effect of KCNJ2 mutations on the CNS has never been studied. OBJECTIVE: To define a potential CNS phenotype in ATS using standardized methods. METHODS: Ten subjects with KCNJ2 mutations and their unaffected siblings were evaluated at the University of California San Francisco General Clinical Research Center. A comprehensive battery of neurocognitive tests was administered to ATS subjects and their unaffected siblings, followed by pairwise analysis of the resultant differences in scores. An EEG was obtained for all ATS subjects. RESULTS: There was no EEG evidence of subclinical seizure activity in any subject. ATS subjects universally had more school difficulties than their siblings, despite similar IQ between the two groups. On formal neurocognitive testing, there was no difference between ATS subjects and their siblings on tests of verbal and visual memory. Assessment of executive functioning revealed ATS subjects scored 1.93 points lower than their siblings on tests of Design Fluency (95% CI -3.46, 0.01; p = 0.052) and made 1.9 more errors (95% CI 0.46, 2.54; p = 0.005). Subjects with ATS scored an average of 5 points lower than their siblings on tests of matrix reasoning (95% CI -8.67, -1.33; p = 0.008). On tests of general ability, ATS subjects achieved much lower scores than their siblings, with an average difference of 9.13 points for reading (95% CI -12.46, 3.21; p = 0.056) and 23.4 points for mathematics (95% CI -42.53, -4.22; p = 0.017). CONCLUSION: Mutations in KCNJ2 are associated with a distinct neurocognitive phenotype, characterized by deficits in executive function and abstract reasoning.

Adolescent↗
PubMed2006

Andersen-Tawil syndrome: prospective cohort analysis and expansion of the phenotype.

Andersen-Tawil syndrome (ATS) is an autosomal dominant multisystem disorder characterized by developmental, cardiac, and neuromuscular abnormalities. Approximately 70% of patients have mutations in KCNJ2, resulting in dysfunction of the inward-rectifying potassium channel Kir2.1. Variable expression complicates the diagnosis of ATS, which in many cases, is not made until years after the first recognized symptom. To better define the distinctive clinical features of ATS and facilitate earlier diagnosis, we conducted a prospective, standardized evaluation of 10 subjects with confirmed KCNJ2 mutations. Detailed anthropometric, neurological, and cardiac evaluations were performed. Using this approach, we identified novel skeletal and dental findings and proposed additional diagnostic criteria for ATS dysmorphology.

Abnormalities, Multiple↗
PubMed2004

Correlating phenotype and genotype in the periodic paralyses.

BACKGROUND: Periodic paralyses and paramyotonia congenita are rare disorders causing disabling weakness and myotonia. Mutations in sodium, calcium, and potassium channels have been recognized as causing disease. OBJECTIVE: To analyze the clinical phenotype of patients with and without discernible genotype and to identify other mutations in ion channel genes associated with disease. METHODS: The authors have reviewed clinical data in patients with a diagnosis of hypokalemic periodic paralysis (56 kindreds, 71 patients), hyperkalemic periodic paralysis (47 kindreds, 99 patients), and paramyotonia congenita (24 kindreds, 56 patients). For those patients without one of the classically known mutations, the authors analyzed the entire coding region of the SCN4A, KCNE3, and KCNJ2 genes and portions of the coding region of the CACNA1S gene in order to identify new mutations. RESULTS: Mutations were identified in approximately two thirds of kindreds with periodic paralysis or paramyotonia congenita. The authors found differences between the disorders and between those with and without identified mutations in terms of age at onset, frequency of attacks, duration of attacks, fixed proximal weakness, precipitants of attacks, myotonia, electrophysiologic studies, serum potassium levels, muscle biopsy, response to potassium administration, and response to treatment with acetazolamide. CONCLUSIONS: Hypokalemic periodic paralysis, hyperkalemic periodic paralysis, and paramyotonia congenita may be distinguished based on clinical data. This series of 226 patients (127 kindreds) confirms some clinical features of this disorder with notable exceptions: In this series, patients without mutations had a less typical clinical presentation including an older age at onset, no changes in diet as a precipitant, and absence of vacuolar myopathy on muscle biopsy.

Adolescent↗
PubMed2003

PIP2 binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome.

BACKGROUND: Mutations in KCNJ2, the gene encoding the inward-rectifying K+ channel Kir2.1, cause the cardiac, skeletal muscle, and developmental phenotypes of Andersen-Tawil syndrome (ATS; also known as Andersen syndrome). Although pathogenic mechanisms have been proposed for select mutations, a common mechanism has not been identified. METHODS: Seventeen probands presenting with symptoms characteristic of ATS were evaluated clinically and screened for mutations in KCNJ2. The results of mutation analysis were combined with those from previously studied subjects to assess the frequency with which KCNJ2 mutations cause ATS. RESULTS: Mutations in KCNJ2 were discovered in nine probands. These included six novel mutations (D71N, T75R, G146D, R189I, G300D, and R312C) as well as previously reported mutations R67W and R218W. Six probands possessed mutations of residues implicated in binding membrane-associated phosphatidylinositol 4,5-bisphosphate (PIP2). In total, mutations in PIP(2)-related residues accounted for disease in 18 of 29 (62%) reported KCNJ2 -based probands with ATS. Also reported is that mutation R67W causes the full clinical triad in two unrelated males. CONCLUSIONS: The novel mutations corresponding to residues involved in Kir2.1 channel-PIP2 interactions presented here as well as the overall frequency of mutations occurring in these residues indicate that defects in PIP2 binding constitute a major pathogenic mechanism of ATS. Furthermore, screening KCNJ2 in patients with the complex phenotypes of ATS was found to be invaluable in establishing or confirming a disease diagnosis as mutations in this gene can be identified in the majority of patients.

Abnormalities, Multiple↗
PubMed2002

Impairment of slow inactivation as a common mechanism for periodic paralysis in DIIS4-S5.

BACKGROUND: Mutations in the human skeletal muscle sodium channels are associated with hyperKPP, hypoKPP, paramyotonia congenita, and potassium-aggravated myotonia. This article describes the clinical manifestations of a patient with hyperKPP carrying a mutation (L689I) occurring in the linker DIIS4-S5 and its functional expression in a mammalian system. OBJECTIVE: To correlate the clinical manifestations of hyperkalemic periodic paralysis (hyperKPP) with the functional expression of a sodium channel mutation. METHODS: The mutation was introduced into a mammalian expression vector and expressed in the human embryonic kidney 293 cells. The functional expression of the L689I and that of the wild-type channels was monitored using the whole cell voltage-clamp technique. RESULTS: There was no change in the kinetics of fast inactivation, and inactivation curves were indistinguishable from that of wild-type channels. However, the L689I mutation caused a hyperpolarizing shift in the voltage dependence of activation and the mutant channels showed an impaired slow inactivation process. In addition, the mutant channels have a larger persistent current at -40 mV where window current may occur. CONCLUSIONS: The L689I mutation has similar effects to the T704M mutation and causes hyperKPP in this family. Because both of these hyperKPP mutations cause episodic muscle weakness, and because patients harboring another mutation (I693T) also can have episodic weakness, it is hypothesized that mutations occurring in this region of the sodium channel may cause episodic weakness through an impaired slow inactivation process coupled with enhanced activation.

Adult↗
PubMed2001

Association of ataxin-7 with the proteasome subunit S4 of the 19S regulatory complex.

Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder characterized by ataxia and selective neuronal cell loss caused by the expansion of a translated CAG repeat encoding a polyglutamine tract in ataxin-7, the SCA7 gene product. To gain insight into ataxin-7 function and to decipher the molecular mechanisms of neurodegeneration in SCA7, a two-hybrid assay was performed to identify ataxin-7 interacting proteins. Herein, we show that ataxin-7 interacts with the ATPase subunit S4 of the proteasomal 19S regulatory complex. The ataxin-7/S4 association is modulated by the length of the polyglutamine tract whereby S4 shows a stronger association with the wild-type allele of ataxin-7. We demonstrate that endogenous ataxin-7 localizes to discrete nuclear foci that also contain additional components of the proteasomal complex. Immunohistochemical analyses suggest alterations either of the distribution or the levels of S4 immunoreactivity in neurons that degenerate in SCA7 brains. Immunoblot analyses demonstrate reduced levels of S4 in SCA7 cerebella without evident alterations in the levels of other proteasome subunits. These results suggest a role for S4 and ubiquitin-mediated proteasomal proteolysis in the molecular pathogenesis of SCA7.

Adenosine Triphosphatases↗
PubMed2001

Polyglutamine-expanded ataxin-7 antagonizes CRX function and induces cone-rod dystrophy in a mouse model of SCA7.

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant disorder caused by a CAG repeat expansion. To determine the mechanism of neurotoxicity, we produced transgenic mice and observed a cone-rod dystrophy. Nuclear inclusions were present, suggesting that the disease pathway involves the nucleus. When yeast two-hybrid assays indicated that cone-rod homeobox protein (CRX) interacts with ataxin-7, we performed further studies to assess this interaction. We found that ataxin-7 and CRX colocalize and coimmunoprecipitate. We observed that polyglutamine-expanded ataxin-7 can dramatically suppress CRX transactivation. In SCA7 transgenic mice, electrophoretic mobility shift assays indicated reduced CRX binding activity, while RT-PCR analysis detected reductions in CRX-regulated genes. Our results suggest that CRX transcription interference accounts for the retinal degeneration in SCA7 and thus may provide an explanation for how cell-type specificity is achieved in this polyglutamine repeat disease.

Age Factors↗
PubMed2001

A novel gene causing a mendelian audiogenic mouse epilepsy.

Frings mice are a model of generalized epilepsy and have seizures in response to loud noises. This phenotype is due to the autosomal recessive inheritance of a single gene on mouse chromosome 13. Here we report the fine genetic and physical mapping of the locus. Sequencing of the region led to identification of a novel gene; mutant mice are homozygous for a single base pair deletion that leads to premature termination of the encoded protein. Interestingly, the mRNA levels of this gene in various tissues are so low that the cDNA has eluded detection by standard library screening approaches. Study of the MASS1 protein will lead to new insights into regulation of neuronal excitability and a new pathway through which dysfunction can lead to epilepsy.

Amino Acid Sequence↗
PubMed2001

Two new genes from the human ATP-binding cassette transporter superfamily, ABCC11 and ABCC12, tandemly duplicated on chromosome 16q12.

Several years ago, we initiated a long-term project of cloning new human ATP-binding cassette (ABC) transporters and linking them to various disease phenotypes. As one of the results of this project, we present two new members of the human ABCC subfamily, ABCC11 and ABCC12. These two new human ABC transporters were fully characterized and mapped to the human chromosome 16q12. With the addition of these two genes, the complete human ABCC subfamily has 12 identified members (ABCC1-12), nine from the multidrug resistance-like subgroup, two from the sulfonylurea receptor subgroup, and the CFTR gene. Phylogenetic analysis determined that ABCC11 and ABCC12 are derived by duplication, and are most closely related to the ABCC5 gene. Genetic variation in some ABCC subfamily members is associated with human inherited diseases, including cystic fibrosis (CFTR/ABCC7), Dubin-Johnson syndrome (ABCC2), pseudoxanthoma elasticum (ABCC6) and familial persistent hyperinsulinemic hypoglycemia of infancy (ABCC8). Since ABCC11 and ABCC12 were mapped to a region harboring gene(s) for paroxysmal kinesigenic choreoathetosis, the two genes represent positional candidates for this disorder.

ATP-Binding Cassette Transporters↗
PubMed2001

Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome.

Andersen's syndrome is characterized by periodic paralysis, cardiac arrhythmias, and dysmorphic features. We have mapped an Andersen's locus to chromosome 17q23 near the inward rectifying potassium channel gene KCNJ2. A missense mutation in KCNJ2 (encoding D71V) was identified in the linked family. Eight additional mutations were identified in unrelated patients. Expression of two of these mutations in Xenopus oocytes revealed loss of function and a dominant negative effect in Kir2.1 current as assayed by voltage-clamp. We conclude that mutations in Kir2.1 cause Andersen's syndrome. These findings suggest that Kir2.1 plays an important role in developmental signaling in addition to its previously recognized function in controlling cell excitability in skeletal muscle and heart.

Alleles↗
PubMed2001

An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome.

Familial advanced sleep phase syndrome (FASPS) is an autosomal dominant circadian rhythm variant; affected individuals are "morning larks" with a 4-hour advance of the sleep, temperature, and melatonin rhythms. Here we report localization of the FASPS gene near the telomere of chromosome 2q. A strong candidate gene (hPer2), a human homolog of the period gene in Drosophila, maps to the same locus. Affected individuals have a serine to glycine mutation within the casein kinase Iepsilon (CKIepsilon) binding region of hPER2, which causes hypophosphorylation by CKIepsilon in vitro. Thus, a variant in human sleep behavior can be attributed to a missense mutation in a clock component, hPER2, which alters the circadian period.

Amino Acid Sequence↗
PubMed2001

Sodium channel inactivation defects are associated with acetazolamide-exacerbated hypokalemic periodic paralysis.

A novel mutation in a family with hypokalemic periodic paralysis is described. The mutation R672S is located in the voltage sensor segment S4 of domain II in the SCN4A gene encoding the human skeletal muscle voltage-gated sodium channel. Functional expression of the R672S channels in human embryonic kidney 293 cells revealed a small but significant hyperpolarizing shift in the steady-state fast inactivation, and a dramatic enhancement in channel slow inactivation. These two defects are mainly due to a slow recovery of the mutant channels from fast and/or slow inactivation. Our data may help explain the mechanism underlying hypokalemic periodic paralysis and the patient's worsening from acetazolamide.

Acetazolamide↗
PubMed2001

Ataxin-7 expression analysis in controls and spinocerebellar ataxia type 7 patients.

Expansion of polymorphic CAG repeats encoding polyglutamine cause at least eight inherited neurodegenerative diseases, including Huntington disease and the spinocerebellar ataxias. However, the pathways by which proteins containing expanded polyglutamine tracts cause disease remain unclear. To gain insight into the function of the SCA7 gene product, ataxin-7, as well as its contribution to cell death in spinocerebellar ataxia type 7 (SCA7), polyclonal antibodies were generated and ataxin-7 expression was examined within neuronal tissues from controls and three SCA7 patients. Immunoblotting demonstrates that ataxin-7 is widely expressed but that expression levels vary between tissues. Immunohistochemical analyses indicate that ataxin-7 is expressed within neurons both affected and unaffected in SCA7 pathology and that subcellular localization varies depending upon the neuronal subtype. Additionally, ataxin-7 staining was detected throughout control retina, including intense staining within the cell bodies and photosensitive outer segments of cone photoreceptors. Anti-ataxin-7 antibodies revealed intranuclear inclusions within surviving inferior olivary and cortical pyramidal neurons, as well as within surviving photoreceptor and ganglion cells of SCA7 patients harboring either 42 or 66 CAG repeats at the SCA7 locus. In contrast, inclusion formation was not detected within neurons of a patient with 41 repeats. This study broadens the current understanding of ataxin-7 localization and incorporates for the first time analysis of late-onset SCA7 patients where polyglutamine tract lengths are relatively shorter and disease course less severe than in previously described infantile-onset cases.

Aged↗
PubMed2000

Paroxysmal kinesigenic dyskinesia and infantile convulsions: clinical and linkage studies.

OBJECTIVE: To clinically characterize affected individuals in families with paroxysmal kinesigenic dyskinesia (PKD), examine the association with infantile convulsions, and confirm linkage to a pericentromeric chromosome 16 locus. BACKGROUND: PKD is characterized by frequent, recurrent attacks of involuntary movement or posturing in response to sudden movement, stress, or excitement. Recently, an autosomal dominant PKD locus on chromosome 16 was identified. METHODS: The authors studied 11 previously unreported families of diverse ethnic background with PKD with or without infantile convulsions and performed linkage analysis with markers spanning the chromosome 16 locus. Detailed clinical questionnaires and interviews were conducted with affected and unaffected family members. RESULTS: Clinical characterization and sampling of 95 individuals in 11 families revealed 44 individuals with paroxysmal dyskinesia, infantile convulsions, or both. Infantile convulsions were surprisingly common, occurring in 9 of 11 families. In only two individuals did generalized seizures occur in later childhood or adulthood. The authors defined a 26-cM region using linkage data in 11 families (maximum lod score 6.63 at theta = 0). Affected individuals in one family showed no evidence for a shared haplotype in this region, implying locus heterogeneity. CONCLUSIONS: Identification and characterization of the PKD/infantile convulsions gene will provide new insight into the pathophysiology of this disorder, which spans the phenotypic spectrum between epilepsy and movement disorder.

Adolescent↗
PubMed2000

Genetic localization of an autosomal dominant leukodystrophy mimicking chronic progressive multiple sclerosis to chromosome 5q31.

The hereditary leukodystrophies represent a group of neurological disorders, in which complete or partial dysmyelination occurs in either the central nervous system (CNS) and/or the peripheral nervous system. Adult-onset autosomal dominant leukodystrophy (ADLD) is a slowly progressive, neurological disorder characterized by symmetrical widespread myelin loss in the CNS, and the phenotype is similar to that of chronic progressive multiple sclerosis. We report clinical, neuroradiological and neuropathological data from the originally reported ADLD family. Furthermore, we have localized the gene that causes ADLD to a 4 cM region on chromosome 5q31. Linkage analysis of this family yielded a LOD score of 5.72 at theta = 0.0 with the microsatellite marker D5S804. Genetic localization will lead to cloning and characterization of the ADLD gene and may yield new insights into myelin biology and demyelinating diseases.

Brain↗